?The holy grail of osteoporosis therapy remains the restoration of ? bone mass??1, and consequent fracture reduction. Current osteoporosis therapies have significant limitations2 and NIAMS objectives include addressing ?why some therapeutic agents become less effective with long-term use and ?exploring opportunities for discovery of newly identified molecular targets for new drug treatments?3. Mice harboring a loss-of-function mutation in the gene encoding the transcription factor Nmp4 are healthy, long-lived, and exhibit an unremarkable skeletal phenotype until challenged with an anabolic stimulus including several classes of osteoporosis therapies, which elicits enhanced bone formation4-8. The absence of a baseline phenotype, combined with the improved response to therapy, affords a unique advantage for developing Nmp4 (or one of its upstream/downstream components) as a safe target to enhance efficacy of existing therapies and identify molecular targets for new therapies. Our goal is to determine how disabling Nmp4 improves the osteoanabolic response to drug treatments, in order to distinguish targetable molecules that can be translated to patients. Our published and preliminary ?omic5, biochemical5-7,11, and bone mechanical data inform our hypothesis that Nmp4 limits the number of osteoprogenitors and regulates the composition, production, and export of the matrix and ultimately bone mechanical properties. Furthermore, loss of Nmp4 in osteogenic cells sharply enhances global mRNA translation, coincident with induction of select portions of the unfolded protein response (UPR), which serve to expand the processing capacity of the ER and facilitate protein secretion, converting the osteoblast into a super-secretory cell11. We propose that these super-secretors release a disproportionately high level of osteocalcin and osteopontin5,7 that contribute to the formation of fracture resistant bone87. Three independent aims will reveal the mechanisms underlying Nmp4 action. Aim #1: identify the specific cell type(s) driving the Nmp4-/- response to anabolic agents. Ovariectomized mice harboring selective genomic deletion (flox) of Nmp4 from MSPCs, osteoblasts, or osteoclasts will be treated with mono- and combination osteoporosis therapies. To target the Nmp4 pathways for pharmacological intervention it is crucial to identify the cell type driving the beneficial effects. Aim #2: determine how Nmp4 regulates osteoblast ribosome biogenesis, global and gene-specific mRNA translation rates of matrix proteins, and strategic portions of the UPR coincident with control of ER expansion. The UPR pathway is a potential therapeutic target for numerous disorders including osteoporosis21-27. Aim #3: determine the matrix and mineral composition of the Nmp4-/- bone in the context of energy dissipation mechanisms subsequent to fatigue and fracture toughness tests28-33. Completion of this aim will provide perspectives into the relationship between the osteoblast secretome and bone material properties. We have a powerful way to magnify the effectiveness of existing osteoporosis therapies and provide novel molecular targets for new therapies.